Dual amyloid cross-seeding reveals steric zipper-facilitated fibrillization and pathological links between protein misfolding diseases

Amyloid cross-seeding, as a result of direct interaction and co-aggregation between different disease-causative peptides, is considered as a main mechanism for the spread of the overlapping pathology across different cells and tissues between different protein-misfolding diseases (PMDs). Despite the biomedical significance of amyloid cross-seeding in amyloidogenesis, it remains a great challenge to discover amyloid cross-seeding systems and reveal their cross-seeding structures and mechanisms. Herein, we are the first to report that GNNQQNY - a short fragment from yeast prion protein Sup35 can cross-seed with both amyloid-b (Ab, associated with Alzheimer's disease) and human islet amyloid polypeptide (hIAPP, associated with type II diabetes) to form beta-structure-rich assemblies and to accelerate amyloid fibrillization. Dry, steric beta-zippers, formed by the two beta-sheets of different amyloid peptides, provide generally interactive and structural motifs to facilitate amyloid cross-seeding. The presence of different steric beta-zippers in a variety of GNNQQNY-Ab and GNNQQNY-hIAPP assemblies also explains amyloid polymorphism. In addition, alteration of steric zipper formation by single-point mutations of GNNQQNY and interactions of GNNQQNY with different Ab and hIAPP seeds leads to different amyloid cross-seeding efficiencies, further confirming the existence of cross-seeding barriers. This work offers a better structural-based understanding of amyloid cross-seeding mechanisms linked to different PMDs.